This application is a 371 of PCT/EP97/04440, filed on Aug. 14, 1997.
This invention relates to 1,2,3,4 tetrahydroquinoline derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. In particular, it relates to 1,2,3,4 tetrahydroquinoline derivatives which are potent and specific antagonists of excitatory amino acids.
EPA0386839 describes 1,2,3,4-tetrahydroquiolines possessing at least one substituent at the 4 position and an acidic group at the 2 position and which are specific antagonists of N-methyl-D-aspartate (NMDA) receptors.
Carling et al, Bioorganic and Medicinal Chemistry Letters Vol 13 pp 65-70 1993 teaches 4-substituted-2-carboxy tetrahydroquinolines having good in vitro affinity for the glycine modulatory site of the NMDA receptor complex but at best only weak in vivo activity. More particularly it teaches that such derivatives substituted at the 4 position by the group CH2CO2H or CH2CONHPh have little or no in vivo activity when administered systemically (ip).
We have found a novel group of 4 substituted 2-carboxy-tetrahydroquinoline derivatives which not only have a good in vitro affinity for the strychnine insensitive glycine binding site associated with the NMDA receptor complex but also good in vivo activity when administered systemically eg intravenously (iv).
Thus the present invention provides a compound of formula (I) 
or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO2R2 or COR2 wherein R2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2;
R1 represents a group (CH2)nCN, xe2x80x94CHxe2x95x90CHR3, (CH2)nNHCOCH2R4 or O(CH2)pNR5R6; R3 represents cyano or the group COR7;
R4 represents alkoxy or a group NHCOR8;
R5 and R6 each represent independently hydrogen or alkyl, or
R5 and R6 together with the nitrogen atom to which they are attached represent a heterocyclic group, or R5 is hydrogen and R6 is the group COR9;
R7 represents an alkoxy, amino or hydroxyl group;
R8 represents a hydrogen atom or optionally substituted alkyl, alkoxy, phenyl, heteroaryl or heterocyclic group;
R9 is the group R8 or the group NR10R11 wherein
R10 represents hydrogen or alkyl group;
R11 represents optionally substituted alkyl, phenyl, heteroaryl, heterocyclic or cycloalkyl group;
n is zero or an integer from 1 to 4; p is an integer from 2 to 4.
In compounds of formula (I) the exocyclic double bond is in the trans (E) configuration.
For use in medicine the salts of the compounds of formula (I) will be physiologically acceptable thereof. Other salts however may be useful in the preparation of the compounds of formula (I) or physiologically acceptable salts thereof. Therefore, unless otherwise stated, references to salts include both physiologically acceptable salts and non-physiologically acceptable salts of compounds of formula (I).
Suitable physiologically acceptable salts of compounds of the invention include base addition salts and where appropriate acid addition salts.
Suitable physiologically acceptable base addition salts of compounds of formula (I) include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium, and magnesium, and ammonium salts, formed with amino acids (e.g. lysine and arginine) and organic bases (e.g. procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methyl glucosamine).
The compounds of formula (I) and/or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates.
Compounds of formula (I) and in particular the base addition salts thereof e.g. sodium salt have been found to have an advantageous profile of solubility in water.
The term alkyl as used herein as a group or part of a group refers to a straight or branched chain alkyl group containing from 1 to 4 carbon atom examples of such groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.
The term optionally substituted alkyl as used herein refers to an alkyl group as defined above and which is substituted by one or more hydroxy, carboxyl, and amino groups.
The term halogen refers to a fluorine, chlorine, bromine or iodine atom.
The term heteroaryl refers to a 5 or 6 membered heteroaryl group in which the 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from oxygen sulphur or nitrogen and the 6-membered heteroaryl group containing 1 or 2 nitrogen atoms.
Examples of suitable heteroaryl groups include furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridinyl, and pyrimidinyl.
The term optionally substituted phenyl refers to a phenyl group substituted with up to 3 substituents selected from halogen, C1-4 alkyl, C1-4 alkoxy, amino,alkylamino,hydroxy, trifluoromethyl, carboxyl or methoxycarbonyl.
The term cycloalkyl refers to a C3-7cycloalkyl group which may optionally be substituted by 1 or 2 C1-4 alkyl groups e.g cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl cycloheptyl or 2-methylcyclohexyl.
The term optionally substituted heterocyclic group refers to 5-7 membered saturated heterocyclic groups containing one or two heteroatoms selected from oxygen, sulphur or nitrogen. Examples of suitable groups containing a single heteroatom include tetrahydropyranyl e.g. 4-tetrahydropyranyl, pyrrolidinyl e.g 2 or 3 pyrrolidinyl, piperidinyl e.g 4- or 3-piperidinyl and N-substituted derivatives therefore (e.g. N-alkyl such as e.g. methyl or N-acyl such as N-alkanoyl e.g. acetyl or N-alkoxycarbonyl e.g. ethoxycarbonyl), piperidino or pyrrolidino. Examples of suitable groups containing 2 heteroatoms include morpholino, thiomophlino or piperazino.
When R5 and R6 together with the nitrogen atom to which they are attached represent an heterocyclic group this is a saturated 5-7 membered ring optionally containing an additional heteroatom selected from oxygen, sulphur or nitrogen.
Examples of such groups include morpholino, 2,6 dimethylmorpholino, piperidino, pyrrolidino, piperazino or N-methylpiperazino.
The compounds of formula(I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 2 position of the 1, 2, 3, 4 tetrahydroquinoline ring system) and other asymmetric carbon atoms are possible in the groups R and R1. Also when R1 is the group CHxe2x95x90CHR3, the group may exist in the cis or trans configuration or mixtures. It is to be understood that all stereoisomers including enantiomers, diastereoisomers and geometric isomers and mixtures thereof are encompassed within the scope of the present invention.
It will be appreciated that the compounds of formula (I) may be produced in vivo by metabolism of a suitable prodrug. Such prodrugs include for example physiologically acceptable metabolically labile esters of compounds of the general formula (I). These may be formed by esterification, for example of any of the carboxylic acid groups in the parent compound of general formula (I) with, where appropriate, prior protection of any other reactive groups present in the molecule, followed by deprotection if required. Examples of such metabolically labile esters include C1-4alkyl esters e.g. methyl or ethyl esters, substituted or unsubstituted aminoalkyl esters (e.g. aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholino)ethyl esters or acyloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g. pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl, 1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-(4-tetrahydropyranyloxy)carbonyloxyethyl or 1-(4-tetrahydropyranyl)carbonyloxyethyl.
For compounds of formula (I) m is conveniently 1 or 2 and within these compounds those wherein R is at the 5 and/or 7 position are preferred.
The group R is conveniently a halogen atom, such as bromine or chlorine and preferably is a chlorine atom.
A preferred group of compounds of formula (I) are those wherein m is 2 and R which is at the 5 and 7 position is bromine or more particularly chlorine.
When R3 is the group COR7, R7 is conveniently hydroxyl, amino or C1-4alkoxy e.g. methoxy, ethoxy, propoxy, butoxy and t-butoxy.
When R4 is the group NHCOR8, R8 is conveniently hydrogen or C1-4alkyl e.g. methyl, ethyl, isopropyl, butyl or isobutyl When R1 is the group O(CH2)pNR5R6. Conveniently R5 and R6 each represent hydrogen or NR5R6 represents a morpholino group, or R5 represents hydrogen and R6 represents COR9 wherein
R9 is hydrogen or C1-4alkyl or the group NH2;
n is conveniently zero, 1 or 2;
p is conveniently 2.
The group R1 may be in the 2, 3 or 4 position in the phenyl ring and is conveniently at the 3 or 4 position. Preferably R1 is at the 4 position.
A preferred class of compounds are those wherein R1 is the group (CH2)nCN (eg. CH2CN), xe2x80x94CHxe2x95x90CHR3 wherein R3 is cyano or COR7 (wherein R7 is C1-4 alkoxy(e.g. t-butoxy) or amino), (CH2)nNHCOCH2R4 (wherein R4 is alkoxy e.g. methoxy or NHCOR8 wherein R8 is hydrogen or C1-4alkyl (e.g. isopropyl)) or O(CH2)pNR5R6 wherein R5 and R6 are hydrogen (e.g. aminoethoxy) or NR5R6 represents morpholino (e.g. morpholino ethoxy) or R5 represents hydrogen and R6 is COR9 wherein R9 is hydrogen or C1-4alkyl e.g isopropyl. Within this class of compounds n is zero, 1 or 2 and more preferably 1; p is 2, 3 or 4 and more preferably 2.
A particularly preferred class of compounds are those wherein R1 is the group CH2CN, xe2x80x94CHxe2x95x90CHR3 (wherein R3 is C1-4alkoxycarbonyl eg butoxycarbonyl, carbamoyl or cyano), (CH2)nNHCOCH2R4 (wherein n is zero and R4 is C1-4alkoxy, eg methoxy or NHCOR8 wherein R8 is C1-4alkyl eg isopropyl), eg R1 is 2-methoxyacetylamino or isobutyrylamino-methylcarbonylamino, or R1 is O(CH2)pNR5R6 (wherein p is 2, R5 is hydrogen and R8 is COR9 wherein R9 is C1-4alkyl eg isopropyl, or NR5R6 represents a morpholino group) eg R1 is 2-isobutyryl aminoethoxy or 2-morpholino-4-ylethoxy.
Specific preferred compounds of the invention include:
(xc2x1) (E) 5,7-Dichloro-4-[4-(2-methoxy-acetylamino)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
(xc2x1) (+,xe2x88x92) (E) 5,7-Dichloro-4-[4-(2-isobutyrylamino-methylcarbonylamino)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
and physiologically acceptable salts e.g. sodium salt, metabolically labile esters or enantiomers thereof.
Further specific preferred compounds of the invention include:
(xc2x1) (E) 5,7-Dichloro-4-(4-cyanomethyl-phenylcarbamoylmethylene)-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
(xc2x1) (E,E) 5,7-Dichloro-4-[4-(2-cyano-vinyl)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
(xc2x1) (E,E) 4-[4-(2-tert-butoxycarbonyl-vinyl)-phenylcarbamoylmethylene]-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
(xc2x1) (E,E) 4-[4-(2-carbamoyl-vinyl)-phenylcarbamoylmethylene]-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
(xc2x1) (E) 5,7-Dichloro-4-[4-(2-isobutyrylamino-ethoxy)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
(xc2x1) (E) 5,7-Dichloro-4-[4-(2-morpholin-4-yl-ethoxy)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid;
and physiologically acceptable salts e.g. sodium salt, metabolically labile esters or enantiomers thereof.
The compounds of formula (I) and/or physiologically acceptable salts thereof are excitatory amino acid antagonists. More particularly they are potent antagonists at the strychnine insensitive glycine binding site associated with the NMDA receptor complex. As such they are potent antagonists of the NMDA receptor complex. These compounds are therefore useful in the treatment or prevention of neurotoxic damage or neurodegenerative diseases. Thus the compounds are useful for the treatment of neurotoxic injury which follows cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospam, hypoglycemia, anaesia, hypoxia, anoxia, perinatal asphyxia cardiac arrest. The compounds are also useful in the treatment of chronic neurodegenerative diseases such as; Huntingdon""s disease, Alzheimer""s senile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type, multi-infarct dementia, status epilecticus, contusive injuries (e.g. spinal cord injury and head injury), viral infection induced neurodegeration (e.g. AIDS, encephalopaties), Down syndrome, epilepsy, schizophrenia, depression, anxiety, pain, migraine, headaches including cluster headaches and or tension headaches, neurogenic bladder, irritative bladder disturbances, drug dependency, including withdrawal symptoms from alcohol, cocaine, opiates, nicotine, benzodiazepine, and emesis.
The potent and selective action of the compound of the invention at the strychnine-insensitive glycine binding site present on the NMDA receptor complex may be readily determined using conventional test procedures. Thus the ability to bind at the strychnine insensitive glycine binding site was determined using the procedure of Kishimoto H et al. J Neurochem 1981, 37 1015-1024. The selectivity of the action of compounds of the invention for the strychnine insensitive glycine site was confirmed in studies at other ionotropic known excitatory amino acid receptors. Thus compounds of the invention were found to show little or no affinity for the kainic acid (kainate) receptor, a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptor or at the NMDA binding site.
Compounds of the invention have also been found to inhibit NMDA induced convulsions in mice using the procedure Chiamulera C et al. Psychopharmacology (1990) 102, 551-552.
The ability of compounds of the invention to inhibit pain may be demonstrated in conventional analgesic screens such as those described by J J Bennett and J K Xue, Pain 1988,41,87-107.
The invention therefore provides for the use of a compound of formula (I) and/or physiologically acceptable salt or metabolically labile ester thereof for use in therapy and in particular use as medicine for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
The invention also provides for the use of a compound of formula (I) and/or a physiologically acceptable salt or metabolically labile ester thereof for the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex.
According to a further aspect, the invention also provides for a method for antagonising the effects of excitatory amino acids upon the NMDA receptor complex, comprising administering to a patient in need thereof an antagonistic amount of a compound of formula (I) and/or a physiologically acceptable salt or metabolically labile ester thereof.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms.
It will further be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated, the route of administration and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician. In general however doses employed for adult human treatment will typically be in the range of 2 to 800 mg per day, dependent upon the route of administration. Thus for parenteral administration a daily dose will typically be in the range 20-100 mg, preferably 60-80 mg per day. For oral administration a daily dose will typically be within the range 200-800 mg, e.g. 400-600 mg per day.
The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day.
While it is possible that, for use in therapy, a compound of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation.
The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or metabolically labile ester thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x98acceptablexe2x80x99 in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The compositions of the invention include those in a form especially formulated for oral, buccal, parenteral, inhalation or insufflation, implant, or rectal administration. Parenteral administration is preferred.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, accacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate, or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; solubilizers such as surfactants for example polysorbates or other agents such as cyclodextrins; and preservatives, for example, methyl or propyl p-hydroxybenzoates or ascorbic acid. The compositions may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
The composition according to the invention may be formulated for parenteral administration by injection or continuous infusion. Formulations for injection may be presented in unit dose form in ampoules, or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
For administration by inhalation the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs, with the use of a suitable propellant, such as dichlorodifluoromethane, tirchlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable carrier such as lactose or starch. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
The compositions according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
Compounds of general formula (I) and salts thereof may be prepared by the general methods outlined hereinafter. In the following description, the groups R, m, R1 are as defined for the compounds of formula (I) unless otherwise stated.
Compounds of formula (I) may be prepared by the cyclisation of a compound of formula (II) in which R12 is a carboxylic protecting group, R13 represents a bromine or iodine atom, R14 represents hydrogen or a nitrogen protecting group and R1 has the meanings defined in formula(I) or a protected derivative thereof. 
In one embodiment of this process the reaction may be carried out using a catalytic amount of a Palladium (O) complex such as tetrakis(triphenylphosphine)palladium and a suitable organic base such as trialkylamine e.g triethylamine or inorganic base, e.g. potassium carbonate. The reaction is conveniently carried out in an aprotic solvent such as acetonitrile or dimethylformamide at a temperature with the range of 60xc2x0 C. to 150xc2x0 C. followed, where necessary or desired, by subsequent removal of the carboxyl protecting group R12 and any protecting group R14.
In a further embodiment of the process the reaction is carried out using a catalytic amount of a Pd(II) salt such as: palladium acetate, in the presence of a suitable organic base such as a trialkyl amine e.g. triethylamine and a triarylphosphine such as triphenylphosphine.
The reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide and preferably with heating, where necessary or desired, by subsequent removal of the carboxyl protecting group R12 and any protecting group R14.
Suitable carboxyl protecting groups R12 for use in this reaction include alkyl, trichloroalkyl, trialkylsilylalkyl, or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
When R14 is nitrogen protecting examples of suitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2-trimethylsilylethoxymethyl.
In a further process of the invention compounds of formula(I), may be prepared by reaction of an activated derivative of the carboxylic acid (III) in which R12 is a carboxyl protecting group and R14 is hydrogen or a nitrogen protecting group as defined in formula (II) 
with the amine(IV) 
wherein R1 has the meaning defined in formula(I) or are protected derivative thereof, followed where necessary by subsequent removal of the carboxyl protecting group R12 and any nitrogen protecting group R14.
Suitable activated derivatives of the carboxyl group include the corresponding acyl halide, mixed anhydride, activated ester such as a thioester or the derivative formed between the carboxylic acid group and a coupling agent such as that used in peptide chemistry, for example carbonyl diimidazole or a diimide such as dicyclohexylcarbodiimide.
The reaction is preferably carried out in an aprotic solvent such as a hydrocarbon, a halohydrocarbon, such as dichloromethane or an ether such as tetrahydrofuran.
Suitable carboxyl protecting groups R12 for use in this reaction include alkyl, trichloroalkyl, trialkylsilylalkyl, or arylmethyl groups such as benzyl, nitrobenzyl or trityl.
When R14 is nitrogen protecting examples of suitable groups include alkoxycarbonyl eg. t-butoxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2-trimethylsilylethoxymethyl.
The activated derivatives of the carboxylic acid (III) may be prepared by conventional means. Particularly suitable activated derivatives for use in this reaction are thioesters such as that derived from pyridine-2-thiol. These esters may conveniently be prepared by treating the carboxylic acid (III) with 2,2xe2x80x2-dithiopyridine and triphenylphosphine in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile.
Compounds of formula (II) may be prepared from compound of formula (V) in which R12 is a carboxyl protecting group and R14 is hydrogen or a nitrogen protecting group as defined in formula (II) and R13 represents a bromine or iodine atom 
by rection with an appropriate phosphorus reagent capable of converting the group CHO into the group: 
followed, where necessary or desired, by removal of the carboxyl protecting group R12 and nitrogen protecting group R14.
In one embodiment of this process the reaction may be carried out using a phoshorus ylide of formula (VI) 
wherein R15 is an alkyl or phenyl group and R1 has the meanings defined in formula(I) or a protected derivative thereof.
The reaction is carried out in an aprotic solvent such as acetonitrile or dimethylformamide at a temperature ranging from xe2x88x9210xc2x0 C. to the reflux temperature of the solvent.
Compounds of formula (V) may be prepared by ozonization of the allyl compound of formula (VII) in which R12 is a carboxyl protecting group, R14 is hydrogen or a nitrogen protecting group as defined above and R13 represents a bromine or iodine atom. 
The reaction may be effected by passing a stream of ozone into a solution of compound of formula (VII) in the presence of dimethyl sulphide or triphenylphosphine in a suitable solvent such as halohydrocarbon e.g dichloromethane at low temperature e.g xe2x88x9278xc2x0 C.
Compounds of formula (VII) wherein R14 is hydrogen atom and R12 is carboxyl protecting group as defined above may be prepared by reaction of the amine(VIII) wherein R13 represents a bromine or iodine atom with the aldehyde (IX) in which R12 is carboxyl protecting group 
followed by addition of allyltributyltin in the presence of Lewis acid such as titanium(IV) chloride or boron trifluoride etherate. The reaction conveniently takes place in a solvent such as hydrocarbon e.g toluene or halogenated hydrocarbon e.g. dichloromethane at a temperature ranging from xe2x88x9278xc2x0 C. to room temperature. Compounds of formula (VII) in which R14 is nitrogen protecting group and R12 is carboxyl protecting group as defined above may be prepared from the compound of formula(VII) wherein R14 represents hydrogen atom using conventional procedure for preparing such protected nitrogen atom.
Compounds of formula (III) may be prepared by the cyclisation of a compound of formula (X) in which R12 is a carboxylic protecting group, R13 represents a bromine or iodine atom, R14 represents hydrogen or a nitrogen protecting group as defined above, and R16 represents a suitable carboxyl protecting group such as a t-butyl group 
using similar reaction conditions for those described above for the reaction of compounds of formula (II), followed by removal of the carboxyl protecting group R16 and where necessary or desired by removal of the nitrogen protecting group R14 The carboxyl protecting group may be removed by conventional procedures. Thus when R16 is a t-butyl group it may be removed by reaction with formic acid.
Compounds of formula (X) may be prepared from compound of formula(V) and a phosphourus ylide (R15)3P=CHCO2R16 in which R15 has the meaning defined in formula (VI) and R16 is as defined above, using similar reaction condition for those described above for the reaction of (V) with compound of formula (VI).
In a further process of the invention compounds of formula(X) may be prepared by reaction of the imino compound(XI), in which R12 is a carboxylic protecting group, R13 represents a bromine or iodine atom, with silane derivatives (XII) 
wherein R17 is a trialkylsilyl group such as tri(C1-4)alkyl group. Example of suitable trialkylsilyl groups include trimethylsilyl and ter-butyldimethylsilyl and R16 represents a suitable protecting group such as t butyl group, in the presence of Lewis acid such as stannic chloride or stannic bromide.
The reaction is conveniently carried out at temperature ranging from xe2x88x9278xc2x0 C. to room temperature in an aprotic solvent such as halohydrocarbons i.e dichloromethane, or aromatic hydrocarbons such as toluene, chlorobenzene or fluorobenzene.
Compounds of formula(XI) may be prepared by reaction of compounds of formula(VIII) and (IX) wherein R13 represents a bromine or iodine atom with the aldehyde (IX) in which R12 is carboxyl protecting group 
The reaction conveniently takes places in a solvent such as hydrocarbon e.g toluene at reflux temperature in the presence of a drying agent such as magnesium sulphate or sodium sulphate.
Compounds of formula (IV), (VI), (VIII) (IX) and (XII) are either known compounds or may be prepared by analogous methods to those used for known compounds.
Specific enantiomers of the compounds of formula(I) may be obtained by resolution of the racemic compounds using conventional procedures such as salts formation with a suitably optically active amine i.e. (R)-xcex1-phenylethylamine, (S) xcex1-phenylethylamine, brucine, cinconidine, quinine, followed by separation of the two diastereoisomer salts obtained and regeneration of the free acid. The two diastereoisomeric salts may be conveniently separated by conventional means such as fractional crystallisation.
Alternatively the required enantiomer may be obtained from racemic compounds of formula(I) by use of chiral HPLC procedures.
In a further process of the invention the required enantiomer may be prepared by esterification of a compound of formula(I) with a suitable chiral alcohol, separating the resultant diastereoisomeric esters by conventional means e.g. chromatography, followed by hydrolysis of the required single diastereomeric ester.
Suitable chiral alcohols for use in the process include S(+)-indanol, S(+)-methyl mandelate, S(xe2x88x92) methyl lactate or R(+) t-butyl lactate.
The diastereoisomeric esters of a compound of formula (I) may be prepared by conventional means such as reaction of the chiral alcohol with an activated derivative of a compound of formula (I) in an aprotic solvent such as ether e.g. tetrahydrofuran.
The activated derivative of a compound of formula(I) may be prepared from a compound of formula(I) using conventional means for preparing activated derivatives of a carboxylic acid groups such as those conveniently used in peptide synthesis.
A convenient method of preparing the diastereoisomeric esters of a compound of formula(I) is to prepare the activated derivative of a compound of formula(I) in the presence of the chiral alcohol.
Thus for example a compound of formula(I) may be treated with the Mitsunobu combination of reagents, i.e. a dialkylazo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphine e.g. triphenylphosphine in the presence of the chiral alcohol.
The reaction conveniently takes place in the presence of a suitable solvent such as an ether (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. diethylether or tetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile (e.g. acetonitrile) or a mixture thereof at a temperature ranging from 0-30xc2x0.
The required single diastereoisomeric ester of a compound of formula(I) substantially free of the other diastereoisomers may be obtained from the mixture thereof by conventional means, for example by the use of conventional chromatographic procedures such as preparative hplc or by fractional crystallization.
The required enantiomer may be prepared from the corresponding single diastereoisomeric ester of a compound of formula(I) by hydrolysis e.g. alkaline hydrolysis. Thus for example the hydrolysis may be carried using an alkali metal hydroxide e.g. sodium hydroxide or lithium hydroxide in a solvent such as an ether e.g. tetrahydrofuran and water.
In any of the above reactions the carboxyl protecting group may be removed by conventional procedures known for removing such groups. Thus compounds where R12 is a benzyl group, this may be removed by hydrolysis using an alkali metal hydroxide e.g. lithium hydroxide or sodium hydroxide in a suitable solvent such as ethanol or isopropanol, water or mixtures thereof, followed, where desired or necessary, by that addition of a suitable acid e.g. hydrochloric acid to give the corresponding free carboxylic acid.
In any of the above reactions the nitrogen protecting group may be removed by conventional procedures known for removing such groups, for example by acid or base hydrolysis. Thus when R14 is alkoxycarbonyl e.g. t-butoxycarbonyl or phenylsulphonyl it may be removed by alkaline hydrolysis using for example lithium hydroxide in a suitable solvent such as tetrahydrofuran or an alkanol e.g. isopropanol. Alternatively the alkoxycarbonyl group may be removed by acid hydrolysis. When R16 is t butyl group this may be removed by hydrolysis using organic acids eg formic acid.
Physiologically acceptable salts of compounds of formula (I) may be prepared by treating the corresponding acid with an appropriate base in a suitable solvent. For example alkali and alkaline metal salts may be prepared from an alkali or alkaline metal hydroxide, or the corresponding carbonate or bicarbonate thereof. Alternatively alkali or alkaline metal salts may be prepared by direct hydrolysis of carboxyl protected derivatives of compounds of formula (I) with the appropriate alkali or alkaline metal hydroxide.
Metabolically labile esters of compounds of formula (I) may be prepared by esterification of the carboxylic acid group or a salt thereof or by trans esterfication using conventional procedures. Thus, for example, acyloxyalkyl esters may be prepared by reacting the free carboxylic acid or a salt thereof with the appropriate acyloxylalkyl halide in a suitable solvent such as dimethylformamide. For the esterifcation of the free carboxyl group this reaction is preferably carried out in the presence of a quaternary ammonium halide such as tetrabutylammonium chloride or benzyltriethylammonium chloride.
Aminoalkyl esters may be prepared by transesterification of a corresponding alkyl ester e.g. methyl or ethyl ester by reaction with the corresponding aminoalkanol at an elevated temperature e.g. 50-150xc2x0.